Human and mouse granzyme A induce a proinflammatory cytokine response.
Granzyme A (GzmA) is considered a major proapoptotic protease. We have discovered that GzmA-induced cell death involves rapid membrane damage that depends on the synergy between micromolar concentrations of GzmA and sublytic perforin (PFN). Ironically, GzmA and GzmB, independent of their catalytic activity, both mediated this swift necrosis. Even without PFN, lower concentrations of human GzmA stimulated monocytic cells to secrete proinflammatory cytokines (interleukin-1beta [IL-1beta], TNFalpha, and IL-6) that were blocked by a caspase-1 inhibitor. Moreover, murine GzmA and GzmA(+) cytotoxic T lymphocytes (CTLs) induce IL-1beta from primary mouse macrophages, and GzmA(-/-) mice resist lipopolysaccharide-induced toxicity. Thus, the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator.
Metkar
Sunil S
SS
Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
Menaa
Cheikh
C
Pardo
Julian
J
Wang
Baikun
B
Wallich
Reinhard
R
Freudenberg
Marina
M
Kim
Stephen
S
Raja
Srikumar M
SM
Shi
Lianfa
L
Simon
Markus M
MM
Froelich
Christopher J
CJ
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D002448:Cell Adhesion; D016923:Cell Death; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D055785:Gene Knockdown Techniques; D053804:Granzymes / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D054353:Perforin / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D020298:U937 Cells
D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D053804:Granzymes